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FXR agonist

A technology of stereoisomers and alkyl groups, applied in the field of FXR receptor agonists, can solve the problems of instability to light and low bioavailability

Pending Publication Date: 2017-08-08
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to natural compounds, the FXR agonists currently developed internationally can be mainly divided into two categories, one is steroids, represented by Obeticholic acid (OCA) from Intercept, which targets non-alcoholic fat Liver indications, which are in clinical phase III; the other category is new molecular entities, such as GW4604 (WO2000 / 037077), which have been developed in the early stage, although they have strong agonistic activity, they are unstable to light and have low bioavailability

Method used

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Examples

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preparation example Construction

[0135] The present invention also provides the preparation method of the compound of formula (I), which includes but not limited to the following process route (wherein, the definition represented by each abbreviation is as follows: DCM: dichloromethane; DMF: N,N-dimethylformaldehyde amide; DMSO: dimethyl sulfoxide; EA: ethyl acetate; MeOH: methanol; PE: petroleum ether; THF: tetrahydrofuran; DIBAL-H: diisobutylaluminum hydride; TsCl: p-toluenesulfonyl chloride)

[0136] Routing:

[0137]

[0138] R 1 , R 2 , R 3 , R 4 , m, n, W, A, Z, E, F, X, Y are as described above, and A' represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0139] The specific exemplary steps are as follows:

[0140] 1. Preparation of Intermediate 1

[0141] Dissolve starting material 1 in an organic solvent (such as ethanol), slowly add starting material 2 in batches, after the addition is complete, add an alkaline solution (such as NaOH solution), heat to 60°C-90°C ...

experiment example 1

[0166] Experimental Example 1: In vitro biochemical analysis of compounds of the present invention

[0167] (1) Test substance: the compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

[0168] (2) Experimental method:

[0169] Dissolve the detection compound in 100% DMSO, dilute 1000 times, take 160nL, then add 3.84μL detection buffer; Target / Antibody mixture, dilute 2 times, then add 8μL solution; add 4.0μL coactivator peptide diluted 4 times ; Incubate at room temperature for 60 minutes; After incubation, detect and analyze data on a fluorescent microplate reader.

[0170] (3) Experimental results and conclusions:

[0171] Table 1 Biochemical analysis of compounds of the present invention

[0172]

[0173] As can be seen from Table 1, the compound of the present invention has a certain stimulant effect on the FXR receptor, and has important effects on the treatment of related diseases such...

experiment example 2

[0174] Experimental example 2: Effects of the compounds of the present invention on the relative expression of BSEP mRNA in HepG2 cells and human hepatocytes

[0175] (1) Test substance: the compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

[0176] PBS: Phosphate buffered saline.

[0177] Control drug: PX-102, which is the racemate of PX-104 (its structure is as described in the background art).

[0178] (2) Experimental method:

[0179] ①Laying cells, adding compounds and collecting cells

[0180] Use trypsin to digest and collect the cells, and measure the cell concentration; according to the counting results, resuspend the cells to a density of 7.5e5cell / mL; inoculate 2 mL of cells in each well of a 6-well cell culture plate; place the culture plate in an incubator, at 37°C, 5%CO 2 Conditioned for 24 hours.

[0181] Use DMSO to dilute the test compound to 12150, 4050, 1350, 450, 150, 5...

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Abstract

The invention relates to a compound shown as formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof. R1, R2, R3, R4, m, n, W, A, Z, E, F, X and Y are defined as the specification. The invention also relates to a preparation method of the compounds, pharmaceutical preparations and application in drugs for treatment and / or prevention of FXR (farnesoid X receptor) mediated nonalcoholic fatty liver diseases, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications, malignant tumors and other related diseases. (formula (I)).

Description

technical field [0001] The present invention relates to FXR receptor agonists, their pharmaceutically acceptable salts, their esters and their stereoisomers, pharmaceutical preparations containing these compounds, and the compounds, their pharmaceutically acceptable salts, their esters and their Stereoisomers, in the preparation of drugs for the treatment and / or prevention of related diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications and malignant tumors mediated by FXR receptors use in . Background technique [0002] FXR receptor (farnesoid X receptor) is a member of the nuclear receptor family of ligand-activated transcription factors and has a typical nuclear receptor structure, namely, a highly conserved DNA binding domain (DBD) at the amino terminal and a ligand binding domain at the carboxyl terminal. (LBD), the amino-terminal ligand-independent transcriptional activation domain (AF1), the carboxy-...

Claims

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Application Information

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IPC IPC(8): C07D413/12A61K31/422A61P1/16A61P3/00A61P3/10A61P35/00A61P25/32A61P1/00A61P9/10A61P3/06A61P7/02A61P29/00A61P31/14A61P31/20
CPCC07D413/12
Inventor 吴永谦
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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